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Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2712-2718
Incidence, Clinical Features, and Outcome of All
Trans-Retinoic Acid Syndrome in 413 Cases of Newly Diagnosed
Acute Promyelocytic Leukemia
S. De Botton,
H. Dombret,
M. Sanz,
J. San Miguel,
D. Caillot,
R. Zittoun,
M. Gardembas,
A. Stamatoulas,
E. Condé,
A. Guerci,
C. Gardin,
K. Geiser,
D. Cony Makhoul,
O. Reman,
J. de la Serna,
F. Lefrere,
C. Chomienne,
C. Chastang,
L. Degos,
P. Fenaux, and
the
European APL Group
From the Service d'Hematologie of the Centre Hospitalier
Universitaire (CHU) of Lille, Paris St Louis, Dijon, Paris Hotel Dieu,
Angers, Roven, Nancy, Paris Beaujon, Bordeaux, Caen, and Paris
Cochin, France; the Departments of Hematology of Valencia, Salamanca,
Santander, and Madrid, Spain; and the Department of Hematology, Bern,
Switzerland.
All trans-retinoic acid (ATRA) syndrome is a
life-threatening complication of uncertain pathogenesis that can occur
during the treatment of acute promyelocytic leukemia (APL) by ATRA.
Since its initial description, however, no large series of ATRA
syndrome has been reported in detail. We analyzed cases of ATRA
syndrome observed in an ongoing European trial of treatment of newly
diagnosed APL. In this trial, patients 65 years of age or less with an
initial white blood cell count (WBC) less than 5,000/µL were
initially randomized between ATRA followed by chemotherapy (CT)
(ATRA CT group) or ATRA with CT started on day 3; patients
with WBC greater than 5,000/µL received ATRA and CT from day 1;
patients aged 66 to 75 received ATRACT. In patients with
initial WBC less than 5,000/µL and allocated to ATRACT, CT
was rapidly added if WBC was greater than 6,000, 10,000, 15,000/µL by
days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during
induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present
before the onset of ATRA. In 11 patients, they occurred upon
recovery from the phase of aplasia due to the addition of CT.
Respiratory distress (89% of the patients), fever (81%), pulmonary
infiltrates (81%), weight gain (50%), pleural effusion (47%), renal
failure (39%), pericardial effusion (19%), cardiac failure (17%),
and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required
mechanical ventilation and two dialysis. A total of 60 patients
received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped
when clinical signs developed in 30 patients. A total of 55 patients
(86%) who experienced ATRA syndrome achieved complete remission (CR),
as compared with 94% of patients who had no ATRA syndrome (P
= .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system
(CNS) bleeding (1 patient). None of the patients who
achieved CR and received ATRA for maintenance had ATRA
syndrome recurrence. No significant predictive factors of ATRA
syndrome, including pretreatment WBC, could be found. Kaplan Meier
estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% ± 10%, 63% ± 8%, and 68% ± 7% in patients
who had ATRA syndrome as compared with 15% ± 3%, 77% ± 2%, and
80% ± 2% in patients who had no ATRA syndrome (P
= .05, P = .003, and P = .03), respectively.
In a stepwise Cox model that also included pretreatment prognostic
variables, ATRA syndrome remained predictive for EFS and survival. In
conclusion, in this multicenter trial where CT was rapidly added to
ATRA in case of high or increasing WBC counts and DXM generally also
used at the earliest clinical sign, the incidence of ATRA syndrome was
15%, but ATRA syndrome was responsible for death in only 1.2% of the
total number of patients treated. However, occurrence of ATRA syndrome
was associated with lower EFS and survival.
© 1998 by The American Society of Hematology.
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